Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

Briz, Verónica; Sepúlveda‐Crespo, Daniel; Diniz, Ana Rita; Borrego, Pedro; Rodés, Berta; Mata, F. Javier de la; Gómez, Rafael; Taveira, Nuno; Muñoz‐Fernández, María Ángeles

doi:10.1039/c5nr03644e

Cited by 33 publications

(29 citation statements)

References 79 publications

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“…New drugs that approach the treatment of HSV-1 from other strategies, such as acting in other points of the viral cycle or mechanisms of action are being researched. In this context, the NPs have shown their inhibitory action against HSV, HIV or Hepatitis [33,35,40,41]. Thus, NPAuG1-S2, NPAuG2-S4, and NPAuG3-S8 were assayed against HSV-1 in neuronal cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…This limitation highlights the need to develop new anti-HSV-1 compounds based on alternative mechanisms of action. A widespread kind of nanoparticles (NPs) have shown great results inhibiting several steps of the viral cycle in HSV-1 and HIV-2 infection [33][34][35], as well as in other latent viruses [36][37][38]. They have a controlled synthesis consisting of a core with several sequential branching units, which present several end-groups [39].…”

Section: Introductionmentioning

confidence: 99%

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Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes Associated Amyloid-βsecretion

et al. 2020

JCM

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Infections caused by HSV-1 and their typical outbreaks invading the nervous system have been related to neurodegenerative diseases. HSV-1 infection may deregulate the balance between the amyloidogenic and non-amyloidogenic pathways, raising the accumulation of amyloid-β peptides, one of the hallmarks in the neurodegenerative diseases. An effective treatment against both, HSV-1 infections and neurodegeneration, is a major therapeutic target. Therefore, gold nanoparticles (NPAus) have been previously studied in immunotherapy, cancer and cellular disruptions with very promising results. Our study demonstrates that a new NPAus family inhibits the HSV-1 infection in a neural-derived SK-N-MC cell line model and that this new NPAus reduces the HSV-1-induced β-secretase activity, as well as amyloid-β accumulation in SK-APP-D1 modifies cell line. We demonstrated that NPAuG3-S8 crosses the blood-brain barrier (BBB) and does not generate cerebral damage to in vivo CD1 mice model. The NPAuG3-S8 could be a promising treatment against neuronal HSV-1 infections and neuronal disorders related to the Aβ peptides.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes Associated Amyloid-βsecretion

et al. 2020

JCM

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“…[7][8][9]17 However, their ability to inhibit other sexually transmitted infections is unknown. In this work, antiviral activity against HSV-2 of eight dendrimers, which previously showed high anti-HIV activity were researched.…”

Section: Screening Of Polyanionic Carbosilane Dendrimers Antiviral Acmentioning

confidence: 99%

“…Carbosilane dendrimers were effective to inhibit HIV infection and transmission within genital mucosa and were safe in mice models. 7,8,14 Thus, potent antiviral activity of these nanosystems against other sexually transmitted pathogens, such as HSV-2, could be extremely important in order to develop broad-spectrum effective microbicides.…”

Section: Introductionmentioning

confidence: 99%

“…7,8,14 They are distinguished from other dendrimers in their high apolarity of central core and high mobility of peripheral branches, features that turn them into outstanding candidates to be used in biomedical applications. Carbosilane dendrimers were effective to inhibit HIV infection and transmission within genital mucosa and were safe in mice models.…”

Section: Introductionmentioning

confidence: 99%

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Prevention of vaginal and rectal herpes simplex virus type 2 transmission in mice: mechanism of antiviral action

Ceña-Díez¹,

Vacas-Córdoba²,

García-Broncano³

et al. 2016

IJN

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Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH–gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.

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Mechanistic Studies of Viral Entry: An Overview of Dendrimer-Based Microbicides As Entry Inhibitors Against Both HIV and HSV-2 Overlapped Infections

et al. 2016

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This review provides an overview of the development of different dendrimers, mainly polyanionic, against human immunodeficiency virus (HIV) and genital herpes (HSV-2) as topical microbicides targeting the viral entry process. Vaginal topical microbicides to prevent sexually transmitted infections such as HIV and HSV-2 are urgently needed. To inhibit HIV/HSV-2 entry processes, new preventive targets have been established to maximize the current therapies against wild-type and drug-resistant viruses. The entry of HIV/HSV-2 into target cells is a multistep process that triggers a cascade of molecular interactions between viral envelope proteins and cell surface receptors. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV/HSV-2. Inhibitors of each entry step have been identified with regard to generations and surface groups, and possible roles for these agents in anti-HIV/HSV-2 therapies have also been discussed. Four potential binding sites for impeding HIV infection (HSPG, DC-SIGN, GSL, and CD4/gp120 inhibitors) and HSV-2 infection (HS, gB, gD, and gH/gL inhibitors) exist according to their mechanisms of action and structures. This review clarifies that inhibition of HIV/HSV-2 entry continues to be a promising target for drug development because nanotechnology can transform the field of HIV/HSV-2 prevention by improving the efficacy of the currently available antiviral treatments.

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Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

Cited by 33 publications

References 79 publications

Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes Associated Amyloid-βsecretion

Gold Nanoparticles Crossing Blood-Brain Barrier Prevent HSV-1 Infection and Reduce Herpes Associated Amyloid-βsecretion

Prevention of vaginal and rectal herpes simplex virus type 2 transmission in mice: mechanism of antiviral action

Mechanistic Studies of Viral Entry: An Overview of Dendrimer-Based Microbicides As Entry Inhibitors Against Both HIV and HSV-2 Overlapped Infections

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